WO2000067813A1 - Articles en polyurethanne stables du point de vue biologique - Google Patents

Articles en polyurethanne stables du point de vue biologique Download PDF

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Publication number
WO2000067813A1
WO2000067813A1 PCT/IE2000/000056 IE0000056W WO0067813A1 WO 2000067813 A1 WO2000067813 A1 WO 2000067813A1 IE 0000056 W IE0000056 W IE 0000056W WO 0067813 A1 WO0067813 A1 WO 0067813A1
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Prior art keywords
implant
diol
foam
reaction
content
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PCT/IE2000/000056
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English (en)
Inventor
Eamon Brady
Ann Marie Cannon
Fergal Farrell
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Salviac Limited
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Publication date
Priority claimed from PCT/IE1999/000038 external-priority patent/WO2000067812A1/fr
Priority claimed from PCT/IE1999/000037 external-priority patent/WO2000067811A1/fr
Application filed by Salviac Limited filed Critical Salviac Limited
Priority to EP00925547A priority Critical patent/EP1176993B1/fr
Priority to AT00925547T priority patent/ATE242017T1/de
Priority to AU44266/00A priority patent/AU4426600A/en
Priority to DE60003178T priority patent/DE60003178T2/de
Publication of WO2000067813A1 publication Critical patent/WO2000067813A1/fr
Priority to US09/985,819 priority patent/US20020072550A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0068—General culture methods using substrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2101/00—Manufacture of cellular products
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2110/00—Foam properties
    • C08G2110/0008—Foam properties flexible
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2110/00—Foam properties
    • C08G2110/0083—Foam properties prepared using water as the sole blowing agent
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2531/00—Microcarriers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers

Definitions

  • This invention relates to biostable biocompatible polyurethane implants suitable for short and long term implantation in vivo.
  • Known medical grade polyether polyurethane elastomers are susceptible to phagocyte mediated Environmental Stress Cracking (ESC). Because of this known surface phenomenon such polyether polyurethanes are not suitable candidates to provide a foam implant.
  • Conventional polyurethane foam structures have ether linkages which are subject to oxidation induced by an inflammatory response in vivo. This is the first stage in ESC which for foam materials ultimately represents a complete loss of material and device integrity.
  • a biostable porous polyurethane foam implant material the material containing isocyanurate linkages derived from diphenyl methane diisocyanate (MDI) and having a cross-linked structure, and a void content of at least 85%, preferably in excess of 90%, most preferably in excess of 95%, and ideally in excess of 97%.
  • MDI diphenyl methane diisocyanate
  • the invention provides a biostable porous polyether or polycarbonate polyurethane article characterised in that the polyurethane is manufactured from diphenyl methane diisocyanate (MDI) with a 2, 4 MDI isomer content of less than 3%, difunctional polytetramethylene ether glycol (PTMEG) or a polycarbonate polyol, a chain extender, water, a cross-linking agent, and a trimerisation agent, a blowing and/or gelling catalyst and a surfactant.
  • MDI diphenyl methane diisocyanate
  • PTMEG difunctional polytetramethylene ether glycol
  • the porous biomaterial is characterised in that it has a void content in excess of 85%, is cross-linked, the hard phase contains isocyanurate linkages and the materials are biostable.
  • the biostability of the materials of the invention is especially surprising in view of the known problems with conventional polyether polyurethanes and the high surface area to volume ratio of the materials.
  • the excellent biostability of the soft phase of the material is attributable, in part, to the method of manufacture.
  • the material is prepared in a manner whereby the molecules in the material are virtually stress free.
  • the stress free configuration of the molecules of the system provides the highest activation energy barrier to degradation.
  • the materials are processed using a reaction blow moulding free rise method.
  • the stability of the hard phase is ensured by the incorporation of highly stable isocyanurate linkages. A high level of cross-linking in the hard phase enhances its stability.
  • cross-linking agent is employed at high concentrations so as to stabilise the foam.
  • These cross linking agents are highly reactive due to the presence of an amine linkage in their structure. They react with isocyanate at an early stage in the curing process. This helps to capture the blow and prevent blow-off.
  • the trimerisation catalyst causes three isocyanates to trimerise into an isocyanurate structure. This adds additional functionality and is particularly important because the reaction is temperature dependent. This reaction is most aggressive in the region of maximum exotherm. This corresponds to the time in the reaction when the blow is at a maximum. This additionally helps to stabilise the foam at the most critical point in the process and together with the cross- linking agent leads to rapid structure building at this time.
  • the high isocyanate index ensures that the isocyanate is in excess and this facilitates the trimerisation reaction and the triethanolamine reaction.
  • the excess isocyanate provides the final cross-linking during the post cure phase of the process. At this stage in the reaction allophanate and/or biuret linkages are formed.
  • the cross-linking agent is an alkanol amine. More preferably the cross-linking agent is triethanolamine.
  • the triethanolamine content is between 1% and 5% of the formulation mass. More preferably the triethanolamine content is between 1% and 3% of the mass of the formulation.
  • trimerisation catalyst is employed.
  • the trimerisation catalyst may be a tertiary amine, an organophosphorous compound, a metal alkyl or a carboxylate. Carboxylates are preferred and potassium acetate is the most preferred trimerisation catalyst.
  • the amount of potassium acetate is between 0.02% and 0.12% of the mass of the formulation. More preferably the potassium acetate content is between 0.06% and 0.07% of the mass of the formulation.
  • the invention also provides a process for preparing an implant of the invention, the processing comprising; preparing an isocyanate terminated prepolymer in an excess of MDI with a 4, 4 MDI isomer content of greater than 97%;
  • a diol reaction mixture comprising a diol, a cross linking agent, a trimerising catalyst, water, a blowing and/ or gelling catalyst, and a surfactant;
  • Fig. 1.1 is a SEM image of Polyether polyurethane biomaterial placed in a chamber with a 0.45 ⁇ m filter, implanted subcutaneously in the rat animal model and explanted after 8 weeks. The integrity of the voids of the biomaterial will be noted. The structure of the voids is similar to that for the control sample (Fig. 1.2) demonstrating no evidence of ESC;
  • Fig. 1.2 is a SEM image of Polyether polyurethane biomaterial control sample which was not implanted in the rat model
  • Fig. 1.3 is a SEM image of Polyether polyurethane biomaterial placed in a chamber with a 0.45 ⁇ m filter, implanted subcutaneously in the rat animal model and explanted after 8 weeks. As in Fig. 1.1, the integrity of the voids of the biomaterial will be noted. The structure of the voids is similar to that for the control sample (Fig. 1.2) demonstrating no evidence of ESC;
  • Fig. 1.4 is a SEM image (at high magnification) of Polyether polyurethane biomaterial placed in a chamber with a 0.45 ⁇ m filter, implanted subcutaneously in the rat animal model and explanted after 8 weeks. The integrity of the void of the biomaterial will be apparent. The structure of the voids is similar to that for the control sample (Fig. 1.2) demonstrating no evidence of ESC;
  • Fig. 1.5 is a SEM image of Polyether polyurethane biomaterial placed in a chamber with a 3.0 ⁇ m filter, implanted subcutaneously in the rat animal model and explanted after 26 weeks. The integrity of the voids of the biomaterial and the cellular deposition on the biomaterial will be noted. There is no evidence of ESC;
  • Fig. 2.1 is a photomicrograph of the scaffold of Example 1 stained with Haemoxylin and Eosin (H&E), 12 weeks following implantation. The presence of numerous macrophage cells throughout the scaffold and the presence of blood capillaries (indicated by the arrow) in the centre of the scaffold will be noted;
  • H&E Haemoxylin and Eosin
  • the invention provides a biostable porous polyether or polycarbonate polyurethane article characterised in that the polyurethane is manufactured from diphenyl methane dissocyanate (MDI) with a 2, 4 MDI isomer content of less than 3%, difunctional polytetramethylene ether glycol (PTMEG) or a polycarbonate polyol, a chain extender, water a cross-linking agent and a trimerisation agent.
  • MDI diphenyl methane dissocyanate
  • PTMEG difunctional polytetramethylene ether glycol
  • the porous biomaterials are characterised in that it has a void content in excess of 80%, is cross-linked, the hard phase contains isocyanurate linkages and the materials are biostable.
  • the biomaterials of this invention have unique physical and chemical characteristics that make them very suitable for in vivo implantation.
  • the materials are especially suitable to transcatheter implantation due to the extremely high void content.
  • the implants may be used, for example, as an occuluder or a tissue bridge.
  • MDI is the preferred isocyanate of this invention.
  • the condensation of aniline with formaldehyde may produce MDI containing 2,4 and 4'4 isomers.
  • MDI is offered in a wide variety of products, which include the 4,4 isomer 'pure' MDI product, and a variety of polymeric MDI for various different applications
  • Crude (polymeric) MDI is the product formed from the initial production stages where no purification has been carried out to separate various isomers and higher polymeric forms.
  • Emerck crude MDI contains the following components: 55% 4,4 and 2,4 diphenylmethane diisocyanate, 25% triisocyanate, 20% polymeric isocyanate. Due to the myriad of structures within the crude material it is preferable to use a pure grade of MDI for materials of this invention. Pure MDI is classified as an isomer mixture of 4,4' diphenylmethane diisocyanate and 2,4' diphenylmethane diisocyanate. For the materials of this invention the 4,4' isomer is preferred.
  • the pure MDI can be obtained as a solid, a solid in flake form or as a liquid.
  • Pure 4,4' -MDI is sensitive to heat and will dimerise.
  • For pure solid MDI storage below 5°C is recommended and although this will slow down the rate of dimerisation, there is still a limited time for which the pure MDI can be stored. Below 5°C a shelf life of approximately 6 months is recommended.
  • the isocyanate in the reaction chamber is in excess. More preferably the isocyanate index is between 1.03 and 1.20. Even more preferably the isocyanate index is between 1.06 and 1.16. Most preferably the isocyanate index is 1.13.
  • the most important characteristics of a polyol for the production of a low density foam are: •
  • the hydroxyl group (or amine) should be reactive to isocyanate.
  • the viscosity should be as low as possible relative to its molecular weight and functionality.
  • the polyol should have a functionality in the region of 3.
  • the reactivity of the hydroxyl group is dependent on whither it is a primary, tertiary, or quaternary -OH group. For example the reactivity of secondary hydroxyl end groups is several times less reactive with isocyanate than primary hydroxyl groups.
  • the viscosity of the polyol needs to be as low as possible.
  • the table below shows the viscosities of a number of commercially available polyols. The viscosity clearly depends on molecular weight and functionality. The importance of viscosity lies in the fact that the resistance to blowing is determined by the viscosity. Polyols with reduced viscosity are preferred for low density applications.
  • the functionality of the polyol is crucial to stabilising the expanded formulation.
  • High functionality increases the rate at which molecular weight is developed.
  • This molecular weight increase prevents the internal pressure of the gas from blowing the foam apart.
  • This molecular weight increase also prevents the foam from shrinking as the blowing gas is liberated during the cell opening phase.
  • the invention provides a range of biostable materials based on these polyols. In particular low density foams using 'tertiary carbon' free polyols are provided.
  • Multifunctional polyols are usually prepared using a trifunctional initiator, such as glycerol or trimethylolpropane. These materials contain tertiary carbons and would be susceptible to attack and degradation by phagocytic agents. The absence of these linkages enhances the biostability of the materials. Difunctional polyols are thus advantageous from an implantation biostability stand point. This is especially important where the implant is of high surface area and low density.
  • High density PTMEG foams have been produced for applications in shoe manufacture.
  • Du Pont have produced PTMEG microfoams with a density range from 250kg/m 3 to 300kg/m 3 .
  • Low density foam is defined per this invention as having a void content in excess of 80%.
  • Soft microcellular polycarbonate urethane foams are also described by Pinchuck EP461 375.
  • the invention provides a range of low density PTMEG and polycarbonate polyol based polyurethanes with properties suitable for long term biomedical implantation.
  • PTMEG The PTMEG materials of this invention capture the excellent resilience properties of PTMEG and overcome the biostability issues of conventional polyether urethanes.
  • PTMEG is the preferred polyether polyol of this invention.
  • PTMEG is manufactured from Polytetrahydrofuran (PTHF) by a ring opening polymerisation technique.
  • PTHF Polytetrahydrofuran
  • the linearity of PTMEG increases the difficulty in preparing low density 3 dimensional porous matrices with this material.
  • the linearity results from the fact that no poly functional initiator is used during the polymerisation step. This is unlike the polymerisation of other polyethers used in polyurethane foam manufacture that can use a trifunctional or higher functionality initiator to increase the functionality of the polyether polyol.
  • the PTMEG polyols used in this invention have molecular weights of 400 -
  • PTMEG is a white waxy solid material at low temperatures and has a melt temperature ranging from 11°C to 43°C depending on the molecular weight of the PTMEG.
  • the quality of PTMEG starting materials is important for the biomaterials of this invention.
  • the preferred molecular weights of the polyols for this application are 650, 1000 and 2000 with minimum polydispersity.
  • the PTMEG starting materials will have characteristics as outlined below;
  • PTMEG has lower reactivity than standard foaming polyols.
  • PTMEG is commercially available with a functionality of 2.
  • Standard PPG foaming polyols have functionalities above 3 and as high as 8.
  • PTMEG is significantly more viscous than standard PPG based foaming polyols
  • the cross-linking agent provides functionality early in the blowing process.
  • the inclusion of a trimerisation catalyst ensures cyclic isocyanurates groups form during the later part of the blowing phase.
  • the incorporation of isocyanurates introduces a further element of cross-linking and provides additional stability to the foam.
  • the trimerisation catalyst lowers the temperature for the formation of isocyanurates.
  • the rate of isocyanurate formation increases with temperature and is thus linked to the exotherm, the material and the mould temperatures.
  • the polycarbonate diols of the invention have the following general characteristics:
  • the polycarbonate diols are difunctional polyols.
  • the diols of the invention are generally manufactured by a reaction of a carbonate with a diol or a mixture of diols.
  • Examples of the polycarbonate polyols used in the invention are disclosed by Greco EP 0 533275 , Lia U.S.
  • Preferred diols are linear aliphatic diols.
  • the polycarbonate has between 4 and 20 carbons between carbonate linkages. More preferably between 4 and 10.
  • the materials and processes of the invention allow for the early expansion of the foam in a low viscosity state. As the formulation reaches full blow molecular weight is developed quickly and this stabilises the expanded material. The rapid development of molecular weight at the time of full blow is achieved by building three separate types of functionality into the formulation.
  • a trimerisation catalyst generates trifunctional isocyanurates at the time of maximum blow. This occurs because of the temperature dependent nature of the trimerisation reaction and it is accelerated by the exotherm generated in the blowing reaction. The materials and mould temperatures are important in optimising this portion of the reaction.
  • the cross-linking agent is a reactive component that has a functionality of three. It forms covalent bonds when reacted with the diisocyanate, resulting in the formation of a three dimensional network within the material.
  • Cross-linking agents can be grouped into three classes, alcohols, amines and alkanol amines.
  • the alkahols include glycerol, trimethylol propane, and sorbitol. As all of these contain tertiary carbons they are not preferred for the manufacture of the biostable foams of the invention.
  • the amines include MBOCA (3,3'-dichloro-4,4'-diamino-diphenylmethane) and diethylenetriamine .
  • Alkanol amines include ethanol amine, diethanolamine and triethanolamine.
  • Alkanol amines are preferred per this invention.
  • a characteristic of these cross- linking agents is that they function as catalysts, thus they maybe classified as reactive catalysts.
  • a high purity grade is preferred (99+%).
  • Water is employed as the blowing agent in the materials of the invention.
  • the quality of the water used in this formulation is important and is controlled.
  • HPLC grade water with a residue on evaporation of ⁇ 0.0005% may be used. However, more preferably deionised water with no detectable oxidisable substances, chlorides, nitrates sulphates and ammonium, ⁇ 0.001% of residue on evaporation, pH 5 - 8 and endotoxin levels ⁇ 0.5EU/ml is used. High pyrogen levels in starting materials of products destined for human implantation should be avoided.
  • the water content of the polyol resin component ranges from 2-5 php (parts per hundred polyol) depending upon the void content of biomaterial required.
  • Amine catalysts are preferred for this invention. Depending on the structure of the amine either the gelling or blowing reaction is favoured. By careful selection of the catalysts a desirable rate between the gelling and blowing reactions can be achieved to yield a low density material.
  • Amine catalysts including but not limited to triethylenediamine, N,N,N'N'- tetramethylhexamethylenediamine, bis(2-dimethylaminoethyl)methyl amine, N- (2-dimethylaminoethyl)-N'-methylpiperazineand N-(2-dimethylaminoethyl)ether can be used.
  • the preferred catalyst system for this invention is Desmorapid PP (From Whitchem), which is a combination of bis(2-dimethylaminoethyl)methyl amine and N-(2-dimethylaminoethyl)-N'-methylpiperazine, with triethylenediamine. The resulting combination yields a strong blowing reaction.
  • a further class of catalysts is based on carboxylates. These promote the trimerisation reaction of the isocyanate and are critical to the formation of the stable foams of the invention.
  • the inclusion of a trimerisation catalyst ensures cyclic isocyanurates groups form during the later part of the blowing phase.
  • the incorporation of isocyanurates introduces a further element of cross-linking and provides additional stability to the foam.
  • the trimerisation catalyst lowers the temperature for the formation of isocyanurates. The rate of isocyanurate formation increases with temperature and is thus linked to the exotherm, the material and the mould temperatures.
  • the trimerisation catalyst causes three isocyanates to trimerise into an isocyanurate structure. This adds additional functionality and is particularly important because the reaction is temperature dependent. This reaction rate is fastest in the region of maximum exotherm. This corresponds to the time in the reaction when the blow is at a maximum. This additionally helps to stabilise the foam at the most critical point in the process and together with the cross-lmking agent leads to rapid structure building at this time.
  • the high isocyanate index ensures that the isocyanate is in excess and this provides raw material for the trimerisation reaction and the cross linking reaction.
  • trimerisation catalyst is employed.
  • the trimerisation catalyst may be a tertiary amine, an organophosphorous compound, a metal alkyl or a carboxylate. Carboxylates are preferred and potassium acetate is the most preferred trimerisation catalyst.
  • the amount of potassium acetate is between 0.02% and 0.12% of the mass of the formulation. More preferably the potassium acetate content is between 0.06% and 0.07% of the mass of the formulation.
  • Catalysts such as potassium acetate, sodium acetate and the like are added to the resin in a solvent carrier.
  • the function of the surfactant is to control the formation and growth of the gas bubbles and with it many processing and final properties of the scaffold.
  • surfactants allow thermo dynamically incompatible components of a polyurethane foam formulation to mix.
  • concentration of gas bubbles formed during the foaming is strongly dependent on the characteristics of the surfactant used.
  • the main demand on the surfactant is the stabilisation of the expanding liquid mixture.
  • the surfactant reduces the surface tension of the liquid mixture and therefore reduces the energy the system needs to facilitate cell formation and growth.
  • a typical silicone surfactant generally has a siloxane backbone formed by dimethyls iloxane units. Polyether groups and/or additional modifications can be attached to the siloxane backbone.
  • Suitable surfactants include BF 2270, BF 8002 from Goldschmidt A.G. Surfactant quantities from 0.30% to about 2% weight percent based on polyol resin may be suitable. More preferably the weight % of the surfactant is between 0.5% and 1.2%.
  • Chain extenders are low molecular weight difunctional compounds. During the reaction hard segments are formed by the reaction of the diisocyanate with the low molecular weight chain extender. Water used as a blowing agent can also be considered a chain extender as it is a low molecular weight difunctional component. Diols are the preferred chain extender.
  • 1-4-butane diol is a preferred chain extender.
  • a high purity grade is required
  • diol chain extenders that can be considered are, but not limited to, ethylene glycol, propylene glycol, 1-6-hexane diol, diethylene glycol, dipropylene glycol .
  • the materials of the invention are manufactured by a quasi-prepolymer method.
  • the diisocyanate is reacted with a portion of polyol to form a relatively low viscosity prepolymer which is then subsequently reacted with the remainder of the polyol, water, various catalysts, surfactants and chain extenders and other ingredients.
  • the key outputs from the preparation of the prepolymer process are the NCO content of the prepolymer and the resulting viscosity of the prepolymer. These outputs are controlled in the process by controlling the temperature and the method of preparation.
  • the prepolymer is preferably prepared at a temperature between 70°C and 80°C. This provides the best control of viscosity and minimises side reactions. Possible undesirable side reactions at this stage include the formation of allophanates and trimerisation.
  • the method in which the prepolymer is prepared has an affect on the viscosity of the prepolymer. If the liquid polyol is added to isocyanate a lower viscosity prepolymer results than if the isocyanate is added to the liquid polyol. This can be explained in terms of the molecular weight distribution within the prepolymer. The addition of the liquid polyol to the isocyanate is the preferred method. The lower the viscosity of the prepolymer the lower the resulting density of the formulation.
  • the polyol is prepared by adding the required quantity of polyol (of the molecular weight required) to a round bottomed flask, placing in the heating mantle and melted. The appropriate volume of water is added and mixed. Appropriate quantities of the remaining components (chain extender, blowing agent, catalysts, surfactant and cross linking agents) are added to the reaction flask and mixed thoroughly for 25 - 30 minutes using a moderate shear rate.
  • the amount of material required too manufacture even the largest implant or scaffold is only tens of grams.
  • the smallest scaffolds per this invention are only a fraction of a gram.
  • the reaction ingredients are metered using precision gear pumps which can deliver an accuracy of O.Olg.
  • the materials of the invention are metered into a mixing chamber.
  • the polyol mixture and isocyanate resin are aggressively mixed in a mixing chamber.
  • the aggressive mixing causes the two incompatible phases to be interspersed. Mixing is crucial to the processes of the invention as it brings the reactive sites to come into close proximity and this facilitates the reactions.
  • Shot mass per this invention varies from as little as 1 gram. More typically the shot size varies from 2g to lOg. More typically from 3-5g.
  • Mixing is an important variable in controlling the size and distribution of the voids. The greater the level of material mixing the smaller the diameter of the voids.
  • shear and turbulence In the design of a mixing chamber it is desirable to generate shear and turbulence. This ensures that there is homogeneity locally in the chamber and at different points in the chamber. Shear mixing is measured indirectly by the speed of the mixer or the shear rate or the relative velocities of the components of the mixing unit or the velocity gradient. The degree of turbulence in the chamber is dependent on the design of the mixing chamber and is very difficult to quantify.
  • the mixing chamber is circular in cross-section
  • An annular space is provided between the chamber outer wall and an inner relative rotational element.
  • the rotational element rotates at speeds in excess of lOOOrpm, preferably between 2000rpm and 6000rpm.
  • the rotational element has slot features, and/or fin features and/or hole features and/or raised features so as to generate shear stresses and turbulence in the mixing chamber.
  • the dispensing step is characterised in that the material is ejected out of the mixing chamber and into a mould.
  • the conditions of the mould facilitate a phenomenon known as "free rise". Free rise describes a process whereby the mixed products are permitted to expand without limitation.
  • the mixed reactants are dispensed into a mould that facilitates at least a nine fold volumetric expansion and as much as a 50 fold expansion of the biomaterial.
  • the mould is vented to allow for free rise and is placed preferably in a carbon dioxide rich oven, which assists in the stabilisation of the materials physical structure.
  • the temperature of the mould should be in excess of the temperature of the reactants. Preferably the mould temperature is between 80°C and 90°C.
  • the mould should be manufactured from a material, which is non-reactive to isocyanate.
  • PTFE, silicone polypropylene and POM are exemplary mould materials.
  • the low density polyurethane biomaterial is placed in a carbon dioxide oven after dispensing into the mould for a minimum of 1 hour.
  • the oven temperature is between 80°C - 90°C but preferably at 80°C. This process is important in that it helps prevent shrinkage of the material and allows virtually all reactive sites within the structure to react.
  • Reticulation of the scaffold can be carried out by crushing. This optional step increases the number of pores per void. It has the disadvantage that reticulated pores will tend to be more irregular in shape.
  • the materials of this invention are two phase materials.
  • the hard phase is generated by the reaction of MDI with small chain molecules and through trimerisation.
  • the small chain molecules are diols, diamines, alkanol amines or water.
  • the chain extenders are diols or water.
  • the second phase of the material is referred to as the soft phase and is composed PTMEG or a polycarbonate polyol.
  • the two phases differ in cohesive energy density.
  • the soft phase typically has a cohesive energy density in the region of 20-22 MPa I/2 while the hard phase typically has a cohesive energy density in the region of 24 -28MPa 1/2 . This allows the two phases separate into distinct domains. This phase separated domain structure confers optimal biocompatibility characteristics to the material.
  • the hard segment content is from 35 % to 65%. More preferably the hard segment content is from 35% to 55%. More ideally the hard segment content is from 40 to 50%.
  • the Hard Segment Content is defined as follows:
  • M is the mass of a material used in or generated by the reaction.
  • the materials of this invention can be manufactured to indentation hardness which match the compliance of tissues in given applications.
  • the materials of example 1 and 2 have characteristics which approximately match those of tissue.
  • porous biostable polytetramethylene oxide polyurethane urea isocyanurate biomaterial a polyol resin and an isocyanate pre-polymer were prepared.
  • the following raw materials were added to a heated round bottom flask and mixed at 50 - 60°C for a minimum of 25 -30 minutes.
  • An isocyanate pre-polymer with an NCO content of 15.6% was prepared by charging flake MDI (Desmodur 44M flakes from Bayer, MDI-2,4' isomer content of 1.37%) into a heated round bottom flask and allowing the flakes to melt. Upon complete melting of the MDI, the PTMEG (Terathane MW 1000) was added and the reaction mixture was stirred at 70 - 80°C for 60 to 90 minutes. Dry nitrogen was purged through the reaction flask at all times to eliminate moisture from the reaction vessel.
  • MDI Desmodur 44M flakes from Bayer, MDI-2,4' isomer content of 1.376%
  • the polyether polyurethane biomaterial was prepared using metering, mixing and dispensing equipment manufactured by 2KM (Germany). The processing temperature of the materials was 40°C and mixing was achieved at a speed of 5000 RPM. The materials were dispensed into a pre heated silicone mould of temperature 80 - 90°C at an isocyanate index of 1.13. The combined shot size of the materials was 2.2g. The mould was placed in a C0 2 vented oven at a temperature of 90°C for a minimum time period of 90 minutes. The biomaterial was reticulated using a hand press.
  • the calculated hard segment content of this material was 42.6 %
  • a sample of the foam was cut using a cutting blade into a rectangular block, ensuring no skin was present on the material.
  • the dimensions were recorded using a calliper and the weight was recorded on an electronic balance.
  • the void content was calculated as 90% based on a solids density of 1200 Kg/m 3 .
  • sample diameter of 20mm The sample was prepared by first cutting the sample with a cutting blade and then lasering the appropriate cylinder from the piece of material.
  • the indentation hardness recorded were 1.14N at 25%, 1.3N at 40% and 4.14N for 65%.
  • the biomaterial was covered with tissue within 4 weeks of implantation.
  • the biomaterial scaffold was implanted in the vasculature of a rabbit for a period of up to 3 months. Again no degradation of the material was observed.
  • porous biostable polytetramethylene oxide polyurethane urea isocyanurate biomaterial a polyol resin and an isocyanate pre-polymer were prepared.
  • the polyol is prepared per example 1 using the following chemicals
  • An isocyanate pre-polymer with a NCO content of 25.0% was prepared as per example 1 using PTMEG polyol (Terathane MW 650).
  • the polytetramethylene oxide polyurethane urea isocyanurate biomaterial was prepared per the method of example 1 at an isocyanate index of 1.13 with the exception that the combined shot size of the components was 1.3g
  • the calculated hard segment content of this material was 51.9 %
  • a rectangular block was cut as per example 1 and weighed.
  • the void content was calculated as 95% again based on a base line density of 1200Kg/m 3 .
  • a polyol resin and an isocyanate pre-polymer were prepared.
  • the polyol is prepared per example 1 using the following chemicals.
  • the isocyanate pre-polymer was prepared as per example 1 using polycarbonate CX 5510 (MW 1000) to produce a prepolymer with an isocyanate content of 15.6%
  • Polycarbonate CX5510 is a random co-polymer comprising hexamethylene carbonate and pentamethylene carbonate sequences of 1000MW.
  • the materials were mixed at an isocyanate index of 1.13 in an open top reaction vessel.
  • the temperature of the materials was 40°C and a mixing speed of
  • a rectangular block was cut as per example 1 and weighed.
  • the void content was calculated as 88% based on a solids density of 1200Kg/m 3 .
  • Indentation hardness values were measured using the same procedure as per example 1. The following results were obtained: 2.3N at 25%, 3.2N at 40% and 7.8N for 65%.

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Abstract

On fabrique cet implant à base de polyéther ou de polyuréthanne poreux stable du point de vue biologique à partir de diisocyanate de diphénylméthane, de polytétraméthylène-éther-glycol ou de polycarbonate-polyol bifonctionnel, d'un catalyseur de trimérisation, d'un allongeur de chaîne, d'eau, d'un agent de réticulation, d'un catalyseur d'expansion et/ou de gélification et d'un tensioactif. Ce biomatériau possède des liaisons isocyanurate et une teneur en vides supérieure à 85 %. L'implant peut être utilisé comme occluseur ou pont tissulaire.
PCT/IE2000/000056 1999-05-07 2000-05-08 Articles en polyurethanne stables du point de vue biologique WO2000067813A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP00925547A EP1176993B1 (fr) 1999-05-07 2000-05-08 Articles en polyurethanne stables du point de vue biologique
AT00925547T ATE242017T1 (de) 1999-05-07 2000-05-08 Biostabile polyurethanprodukte
AU44266/00A AU4426600A (en) 1999-05-07 2000-05-08 Biostable polyurethane products
DE60003178T DE60003178T2 (de) 1999-05-07 2000-05-08 Biostabile polyurethanprodukte
US09/985,819 US20020072550A1 (en) 1999-05-07 2001-11-06 Biostable polyurethane products

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IEPCT/IE99/00038 1999-05-07
IEPCT/IE99/00037 1999-05-07
PCT/IE1999/000038 WO2000067812A1 (fr) 1999-05-07 1999-05-07 Biostabilite de structures polymeres
PCT/IE1999/000037 WO2000067811A1 (fr) 1999-05-07 1999-05-07 Produit de polyether-polyurethane biostable

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WO2000067813A1 true WO2000067813A1 (fr) 2000-11-16

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PCT/IE2000/000059 WO2000067815A1 (fr) 1999-05-07 2000-05-08 Charpente pour genie tissulaire
PCT/IE2000/000058 WO2000067814A1 (fr) 1999-05-07 2000-05-08 Biostabilite de structures polymeriques
PCT/IE2000/000056 WO2000067813A1 (fr) 1999-05-07 2000-05-08 Articles en polyurethanne stables du point de vue biologique

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PCT/IE2000/000058 WO2000067814A1 (fr) 1999-05-07 2000-05-08 Biostabilite de structures polymeriques

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AU (3) AU4606600A (fr)
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US8445581B2 (en) 2006-08-02 2013-05-21 Polynovo Biomaterials Pty Limited Biocompatible polymer compositions
US8357767B2 (en) 2007-10-03 2013-01-22 Polynovo Biomaterials Limited High modulus polyurethane and polyurethane/urea compositions
CN108276556A (zh) * 2018-02-06 2018-07-13 昆明医科大学 医用聚氨酯材料及其制备方法和修复支架
CN108276556B (zh) * 2018-02-06 2021-04-27 昆明医科大学 医用聚氨酯材料及其制备方法和修复支架

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US20020072550A1 (en) 2002-06-13
DE60003178T2 (de) 2004-04-08
EP1176994A1 (fr) 2002-02-06
EP1176995A1 (fr) 2002-02-06
WO2000067815A1 (fr) 2000-11-16
AU4606700A (en) 2000-11-21
US8168431B2 (en) 2012-05-01
WO2000067814A1 (fr) 2000-11-16
EP1176993B1 (fr) 2003-06-04
AU4606600A (en) 2000-11-21
US20090163612A1 (en) 2009-06-25
AU4426600A (en) 2000-11-21
EP1176993A1 (fr) 2002-02-06
DE60003178D1 (de) 2003-07-10
US20020072584A1 (en) 2002-06-13
US20070003594A1 (en) 2007-01-04

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